Project Summary/Abstract. A fundamental problem this DP1 project will address is the inability of imaging at single molecular or cellular level deep in a living body (animal or human). I plan to enable in vivo ?molecular infrared vision? that detects deep-near-infrared fluorescence for peering into a living human at centimeters depth for imaging down to the single molecules, cells and micro-vasculatures, essentially turning a living body transparent. This could greatly empower human vision for biology in the lab and medicine in the clinic, broadly impacting neuroscience, cancer and cardiovascular disease fields. A limitation of deep tissue imaging modalities for animal models and human has been the lack of high resolution and molecular specificity at single cell level. Optical imaging utilizing fluorescence is capable of high spatial resolution and has revolutionized biological investigations at molecular level. However, a major pitfall of fluorescence imaging has been superficial depth due to scattering and autofluorescence. The PI?s lab has pioneered imaging in the 1000-1700 nm window for through-skull single-vessel imaging with micron-scale resolution. But tissue imaging depth for high resolution is still limited at ~ 4 mm. This work plans to enable fluorescence imaging in a unique, deep near-infrared (dNIR) window of > 2000 nm to turn biological tissues largely transparent with little scattering, for imaging and tracking of biological processes at centimeters depth down to single cell level. Based on chemistry and nanoscience expertise of the PI, this DP1 will innovate chemical synthesis of novel infrared emitting molecular and nanomaterial fluorophores deep in the near infrared (2100-2400 nm), and innovate new dNIR imaging instrumentation. The deep-near-infrared imaging will be used to enable human vision to glean biological structures and processes at the molecular and cellular scale at centimeters depth in a living body with near-zero endogenous background. It could greatly facilitate basic science and clinical disease diagnostics and interventions in areas of neuroscience, cancer and cardiovascular diseases. Examples include, (1) Imaging of single neuron in action under electrical or chemical stimuli at centimeters depth in a brain without craniotomy in mice and human. (2) Record real-time movies of blood flows at single vessel level in the brain following stroke or traumatic brain injury; Assess brain damage, repair/treatment effects at the cellular level. (3) Single-cell tracking during stem cell based therapy. (4) 3D molecular imaging in living tissues of animal models and human. (5) Molecular imaging of cancer down to single tumor cell level in vivo. (6) Translation into clinics for sentinel lymph node mapping, cancer imaging, and imaging guided surgery with single-cell resolution, achieving unprecedented clarity of tumor margin. This DP1 Project will integrate chemistry, physics, materials science and medicine and broadly collaborate with experts and leaders in chemistry, neuroscience, cancer and cardiovascular diseases.